RTS,S/AS01E immunization increases antibody responses to vaccine-unrelated Plasmodium falciparum antigens associated with protection against clinical malaria in African children: a case-control study
Carlota Dobaño,
Itziar Ubillos,
Chenjerai Jairoce,
Ben Gyan,
Marta Vidal,
Alfons Jiménez,
Rebeca Santano,
David Dosoo,
Augusto J. Nhabomba,
Aintzane Ayestaran,
Ruth Aguilar,
Nana Aba Williams,
Núria Díez-Padrisa,
David Lanar,
Virander Chauhan,
Chetan Chitnis,
Sheetij Dutta,
Deepak Gaur,
Evelina Angov,
Kwaku Poku Asante,
Seth Owusu-Agyei,
Clarissa Valim,
Benoit Gamain,
Ross L. Coppel,
David Cavanagh,
James G. Beeson,
Joseph J. Campo,
Gemma Moncunill
Affiliations
Carlota Dobaño
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153
Itziar Ubillos
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153
Chenjerai Jairoce
Centro de Investigação em Saúde de Manhiça (CISM)
Ben Gyan
Noguchi Memorial Institute for Medical Research, University of Ghana
Marta Vidal
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153
Alfons Jiménez
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153
Rebeca Santano
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153
David Dosoo
Kintampo Health Research Centre
Augusto J. Nhabomba
Centro de Investigação em Saúde de Manhiça (CISM)
Aintzane Ayestaran
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153
Ruth Aguilar
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153
Nana Aba Williams
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153
Núria Díez-Padrisa
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153
David Lanar
Malaria Vaccine Branch, Walter Reed Army Institute of Research
Virander Chauhan
Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Chetan Chitnis
Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Sheetij Dutta
Malaria Vaccine Branch, Walter Reed Army Institute of Research
Deepak Gaur
Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Evelina Angov
Malaria Vaccine Branch, Walter Reed Army Institute of Research
Kwaku Poku Asante
Kintampo Health Research Centre
Seth Owusu-Agyei
Kintampo Health Research Centre
Clarissa Valim
Department of Osteopathic Medical Specialties, Michigan State University
Benoit Gamain
Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge UMR_S1134, Laboratoire d’Excellence GR-Ex
Ross L. Coppel
Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University
David Cavanagh
Institute of Immunology & Infection Research and Centre for Immunity, Infection & Evolution, Ashworth Laboratories, School of Biological Sciences, University of Edinburgh
James G. Beeson
Macfarlane Burnet Institute for Medical Research and Public Health
Joseph J. Campo
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153
Gemma Moncunill
ISGlobal, Hospital Clínic - Universitat de Barcelona, Carrer Rosselló 153
Abstract Background Vaccination and naturally acquired immunity against microbial pathogens may have complex interactions that influence disease outcomes. To date, only vaccine-specific immune responses have routinely been investigated in malaria vaccine trials conducted in endemic areas. We hypothesized that RTS,S/A01E immunization affects acquisition of antibodies to Plasmodium falciparum antigens not included in the vaccine and that such responses have an impact on overall malaria protective immunity. Methods We evaluated IgM and IgG responses to 38 P. falciparum proteins putatively involved in naturally acquired immunity to malaria in 195 young children participating in a case-control study nested within the African phase 3 clinical trial of RTS,S/AS01E (MAL055 NCT00866619) in two sites of different transmission intensity (Kintampo high and Manhiça moderate/low). We measured antibody levels by quantitative suspension array technology and applied regression models, multimarker analysis, and machine learning techniques to analyze factors affecting their levels and correlates of protection. Results RTS,S/AS01E immunization decreased antibody responses to parasite antigens considered as markers of exposure (MSP142, AMA1) and levels correlated with risk of clinical malaria over 1-year follow-up. In addition, we show for the first time that RTS,S vaccination increased IgG levels to a specific group of pre-erythrocytic and blood-stage antigens (MSP5, MSP1 block 2, RH4.2, EBA140, and SSP2/TRAP) which levels correlated with protection against clinical malaria (odds ratio [95% confidence interval] 0.53 [0.3–0.93], p = 0.03, for MSP1; 0.52 [0.26–0.98], p = 0.05, for SSP2) in multivariable logistic regression analyses. Conclusions Increased antibody responses to specific P. falciparum antigens in subjects immunized with this partially efficacious vaccine upon natural infection may contribute to overall protective immunity against malaria. Inclusion of such antigens in multivalent constructs could result in more efficacious second-generation multistage vaccines.
